eMedicine Specialties > Neurology > Neurological Infections

Tuberculous Meningitis

Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
Contributor Information and Disclosures

Updated: Dec 4, 2008

Introduction

Background

Skeletal tuberculosis (TB) was present in Egypt as early as 3500 BCE. TB is also described in ancient Chinese and Indian texts. Presently, more than 2 billion people in the world are infected with TB (ie, one third of the world's population), of which approximately 10% will develop clinical disease. The incidence of CNS TB is related to the prevalence of TB in the community, and it is still the most common type of chronic CNS infection in developing countries.

Despite great advances in immunology, microbiology, and drug development, TB remains among the great public health challenges. Poverty; lack of functioning public health infrastructure; lack of funding to support basic research aimed at developing new drugs, diagnostics, and vaccines; and the co-epidemic of HIV continue to fuel the ongoing epidemic of TB.

Pathophysiology

Many of the symptoms, signs, and sequelae of tuberculous meningitis (TBM) are the result of an immunologically directed inflammatory reaction to the infection. The development of TBM is a 2-step process. Mycobacterium tuberculosis bacilli enter the host by droplet inhalation, the initial point of infection being the alveolar macrophages. Localized infection escalates within the lungs, with dissemination to the regional lymph nodes to produce the primary complex. During this stage, a short but significant bacteremia is present that can seed tubercle bacilli to other organs in the body.

In persons who develop TBM, bacilli seed to the meninges or brain parenchyma, resulting in the formation of small subpial or subependymal foci of metastatic caseous lesions. These are termed Rich foci, after the original pathologic studies of Rich and McCordick.¹ Tuberculous pneumonia develops with heavier and more prolonged tuberculous bacteremia. Dissemination to the CNS is more likely, particularly if miliary TB develops.

The second step in the development of TBM is an increase in size of a Rich focus until it ruptures into the subarachnoid space. The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement. Tubercles rupturing into the subarachnoid space cause meningitis. Those deeper in the brain or spinal cord parenchyma cause tuberculomas or abscesses. While an abscess or hematoma can rupture into the ventricle, a Rich focus does not.

A thick gelatinous exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. Basal meningitis accounts for the frequent dysfunction of cranial nerves (CNs) III, VI, and VII, eventually leading to obstructive hydrocephalus from obstruction of basilar cisterns. Subsequent neurological pathology is produced by 3 general processes: adhesion formation, obliterative vasculitis, and encephalitis or myelitis.

Tuberculomas are conglomerate caseous foci within the substance of the brain (see Media file 1). Centrally located, active lesions may reach considerable size without producing meningitis.¹ Under conditions of poor host resistance, this process may result in focal areas of cerebritis or frank abscess formation, but the usual course is coalescence of caseous foci and fibrous encapsulation (ie, tuberculoma). Paradoxical development or enlargement of tuberculomas during antituberculous chemotherapy has also been reported; it possibly has an immunological basis.²

In the tuberculous process, the spinal meninges may be involved, owing to the spread of infection from intracranial meningitis, primary spinal meningitis in isolation as a result of a tuberculous focus on the surface of the cord rupturing into the subarachnoid space, or transdural extension of infection from caries of the spine.

Pathologically, a gross granulomatous exudate fills the subarachnoid space and extends over several segments. Vasculitis involving arteries and veins occurs, sometimes resulting in ischemic spinal cord infarction.

The earliest lesion in the vertebra is invariably due to hematogenous spread, often involving the body of the vertebra near an intervertebral disk. The intervertebral disk is almost always involved with the spread of the disease to the adjacent vertebra and eventually along the anterior or posterior longitudinal ligaments or through the end plate. Soon, a cold abscess develops, either as a paraspinal abscess in the dorsal and lumbar regions or as a retropharyngeal abscess in the cervical region. As the disease progresses, increasing decalcification and erosion result in progressive collapse of the bone and destruction of intervertebral disks, involving as many as 3-10 vertebrae in one lesion, resulting in kyphosis. The abscess may rupture intraspinally, resulting in primary spinal meningitis, hyperplastic peripachymeningitis, intraspinal abscess, or tuberculoma.

Pathological effects

Papilledema is the most common visual effect of TBM. In children, papilledema may progress to primary optic atrophy and blindness resulting from direct involvement of the optic nerves and chiasma by basal exudates (ie, opticochiasmatic arachnoiditis). In adults, papilledema may progress more commonly to secondary optic atrophy, provided the patient survives long enough. Other causes of visual impairment include chorioretinitis, optic neuritis, internuclear ophthalmoplegia, and, occasionally, an abrupt onset of painful ophthalmoplegia.

CN VI is affected most frequently by TBM, followed by CNs III, IV, VII, and, less commonly, CNs II, VIII, X, XI, and XII.³

Sudden onset of focal neurological deficits, including monoplegia, hemiplegia, aphasia, and tetraparesis, has been reported. Although these could be postictal phenomena, they mostly are due to vasculitic changes resulting in ischemia. While some of these could be the result of proliferative arachnoiditis or hydrocephalus, vasculitis still appears to be the leading cause.

Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels that traverse the basilar or spinal exudate or lie within the brain substance. Mycobacterium also may invade the adventitia directly and initiate the process of vasculitis. An early neutrophilic reaction is followed by infiltration of lymphocytes, plasma cells, and macrophages, leading to progressive destruction of the adventitia, disruption of elastic fibers, and, finally, intimal destruction. Eventually, fibrinoid degeneration within small arteries and veins produces aneurysms, multiple thrombi, and focal hemorrhages, alone or in combination.⁴

Tremor is the most common movement disorder seen in the course of TBM. In a smaller percentage of patients, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than in adults. In addition, myoclonus and cerebellar dysfunction have been observed. Deep vascular lesions are more common among patients with movement disorders.

Frequency

United States

TB is the seventh leading cause of death and disability worldwide. In 1997, TBM was the fifth most common form of extrapulmonary TB. TBM accounted for 5.2% (186) of all cases of exclusively extrapulmonary disease and 0.7% of all reported cases of TB. The 2003 "Tuberculosis Advocacy Report" from the World Health Organization stated that 8 million new cases of TB are reported annually and 2 million deaths occur each year.⁵

More recent data suggest that TBM accounts for 2.1% of pediatric cases and 9.1% of extrapulmonary TB cases.⁶ TB accounts for approximately 0.04% of all cases of chronic suppurative otitis media.⁷ The "Tuberculosis Advocacy Report" of 2003 suggests the persistence of TB otitis, as well as possibly an increase in the incidence of TB otitis. Tuberculomas account for 10-30% of intracranial masses in TB-endemic areas.

Data published in 2000 revealed that the risk increased with age across racial and ethnic groups and that case rates were consistently higher in minority racial and ethnic groups than in non-Hispanic whites. Case rates in Asians and Pacific Islanders were the highest, particularly in adults. In 2000, approximately 75% of all reported TB cases occurred in racial and ethnic minorities, including 32% in non-Hispanic blacks, 23% in Hispanics, 21% in Asians and Pacific Islanders, and 1% in Native Americans and Alaskan Natives. Approximately 22% of all reported cases occurred in non-Hispanic whites.

Several important factors likely contribute to the disproportionate burden of TB in minorities. In foreign-born persons from countries where TB is common, active TB disease may result from infection acquired in the country of origin. Approximately 95% of cases in the Asian/Pacific Islander group occurred in foreign-born persons, compared with 70% of cases in Hispanics and 20% of cases in non-Hispanic blacks. In racial and ethnic minorities, unequal distribution of TB risk factors, such as HIV infection, also may contribute to an increased exposure to TB or to the risk of developing active TB once infected with M tuberculosis. However, much of the increased risk of TB in minorities has been linked to lower socioeconomic status and the effects of crowding, particularly among US-born persons.

International

The worldwide prevalence of TB in children is difficult to assess because data are scarce and poorly organized. The available reports grossly underestimate the true incidence. Lack of surveillance testing in most areas of the world restricts the ability to assess the prevalence of the disease. In many areas of Africa and Asia, the annual incidence of TB infection for all ages is approximately 2%, which would yield an estimated 200 cases of TB per 10,000 population per year. Approximately 15-20% of these cases occur in children younger than 15 years. In the developing world, 10-20% of persons who die of TB are children.

The developing world has 1.3 million cases of TB and 40,000 TB-related deaths annually among children younger than 15 years. TBM complicates approximately 1 of every 300 untreated primary TB infections.

Mortality/Morbidity

• Mortality: The number of deaths due to TB has decreased dramatically since 1953. In 1953, 19,707 deaths from TB were reported in the United States, for a rate of 12.4 deaths per 100,000 population. In 1997, 1,166 deaths were reported, for a rate of 0.4 deaths per 100,000 population. The number of TB deaths and the TB death rate increased slightly during a recent TB resurgence, reaching a high in 1989 of 1,970 deaths and a rate of 0.8 deaths per 100,000 population before decreasing again.
• Morbidity: Between 1969 and 1973, TBM accounted for approximately 4.5% of the total extrapulmonary TB morbidity in the United States. Between 1975 and 1990, 3,083 cases of TBM were reported by the US Centers for Disease Control and Prevention (CDC), an average of 193 cases per year, accounting for 4.7% of total extrapulmonary TB cases during that 16-year period. In 1990, however, 284 cases of TBM were reported, constituting 6.2% of the morbidity attributed to extrapulmonary TB. This increase in TBM was most likely due to increasing CNS TB among patients with HIV/AIDS and to the increasing incidence of TB among infants, children, and young adults of minority populations.

Race

Rates in whites are lowest at all age groups, and rates in Asians and Pacific Islanders are the highest. Rates among Blacks, Hispanics, and Native Americans/Alaskan Natives are intermediate. Black men have appreciably higher rates than Hispanic and Native American/Alaskan Native men, except in the oldest age group.

Sex

Among persons younger than 20 years, TB infection rates are similar for both sexes; the lowest rates are observed in children aged 5-14 years. During adulthood, TB infection rates are consistently higher for men than for women; the male-to-female ratio is approximately 2:1.

Age

Prior to the appearance of HIV, the most important determinant for the development of TBM was age.

• In populations with a low prevalence of TB, most cases of TBM occur in adults. In the United States in 1996, case rates were low in infancy and decreased somewhat during early childhood. After the age of puberty, they showed a steady increase with age.
• In general, however, TBM is more common in children than in adults, especially in the first 5 years of life. In fact, children aged 0-5 years are affected more commonly with TBM than any other age group. TBM is uncommon, however, in children younger than 6 months and almost unheard of in infants younger than 3 months because the causative pathological sequence takes at least 3 months to develop.
• Children aged 5-14 years often have been referred to as the favored age because they have lower rates of TB than any other age group.
• Childhood TB has a limited influence on the immediate epidemiology of the disease because children rarely are a source of infection to others.
• Younger children are more likely to develop meningeal, disseminated, or lymphatic TB, whereas adolescents more frequently present with pleural, genitourinary, or peritoneal disease.

Clinical

History

Tuberculous meningitis (TBM) is difficult to diagnose, and a high index of suspicion is needed to make an early diagnosis.

• Elucidate the following:
  • Inquire about the patient's medical and social history, including recent contact with patients with TB.
  • Elicit any known history of a positive result on the purified protein derivative test, especially a recent conversion.
  • Determine if the patient has a history of immunosuppression from a known disease or from drug therapy.
  • Check if the patient has a negative history for BCG vaccination.
• Usually, the prodrome is nonspecific, including headache, vomiting, photophobia, and fever. In one study, only 2% of patients reported meningitic symptoms. The duration of presenting symptoms may vary from 1 day to 9 months, although 55% presented with symptoms of less than 2 weeks in duration.
• In an immunocompetent individual, CNS TB usually takes the form of meningitis that causes an acute-to-subacute illness characterized by fever, headache, drowsiness, meningism, and confusion over a period of approximately 2-3 weeks.
  • During the prodromal period, nonspecific symptoms are present, including fatigue, malaise, myalgia, and fever.
  • Often, in the first stage of meningitis, patients have infection of the upper respiratory tract, a fact that should be remembered when the concurrent fever and irritability or lethargy seem out of proportion to the obvious infection or when general symptoms persist after improvement in the local manifestations. Fever and headache can be absent in 25% of patients and malaise can be absent in as many as 60% of patients. Headache and mental status changes are much more common in elderly persons.
• Visual symptoms include visual impairment or blindness and, occasionally, abrupt onset of painful ophthalmoplegia. Ocular tuberculosis presents a form of granulomatous uveitis. Delayed or wrong diagnosis may be detrimental on the ocular structures and the health of the individual.¹⁰
• Sudden onset of focal neurologic deficits, including monoplegia, hemiplegia, aphasia, and tetraparesis, has been reported.
• Tremor and, less commonly, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than adults. Myoclonus and cerebellar dysfunction have also occurred.
• The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a common complication and is linked to a poor prognosis.
• Less frequent presentations include atypical febrile seizures in children, isolated CN palsies, bilateral papilledema, and acute confusional state.
• Tuberculous spinal meningitis may manifest as an acute, subacute, or chronic form.
  • The clinical picture in primary spinal meningitis is often characterized by myelopathy, with progressive ascending paralysis, eventually resulting in basal meningitis and associated sequelae.
  • In some cases with acute onset, in addition to variable constitutional symptoms, patients develop acute paraplegia with sensory deficits and urinary retention. The clinical picture often mimics transverse myelitis or Guillain-Barré syndrome.
  • The subacute form is often dominated by myeloradiculopathy, with radicular pain and progressive paraplegia or tetraplegia.
  • A less virulent chronic form might mimic a very slowly progressive spinal cord compression or a nonspecific arachnoiditis.
  • The dorsal cord seems to be affected most commonly, followed by the lumbar and the cervical regions.
• Tuberculous spondylitis is also known as Pott disease or spinal caries.
  • In regions where the disease is endemic, such as Asia and Africa, this condition still accounts for 30-50% of all cases of compressive myelopathy resulting in paraplegia. Spinal TB also accounts for approximately 50% of all bone and joint TB cases.
  • In the lumbar region, tuberculous spondylitis may result in a psoas abscess that often calcifies.
  • It usually runs a subacute or a chronic course, with back pain and fever and variable neurological deficits.
  • Spondylitis can also result in various symptoms, including local and radicular pain, limb motor and sensory loss, and sphincter disturbances.
  • Eventually, complete spinal cord compression with paraplegia, the most dreaded complication, may supervene.
• Tuberculous radiculomyelitis (TBRM) is a complication of TBM that has been reported only rarely in the modern medical literature.
  • TBRM develops at various periods after TBM, even in adequately treated patients after sterilization of the cerebrospinal fluid (CSF).
  • The most common symptoms are subacute paraparesis, radicular pain, bladder disturbance, and subsequent paralysis.
  • As in other forms of paradoxical reactions to anti-TB treatment, evidence shows that steroid treatment might have a beneficial effect.
• Two rare forms of TBM are serous TB meningitis and TB encephalopathy.
  • Serous TB meningitis is characterized by signs and symptoms of a mild meningitis with spontaneous recovery.
  • TB encephalopathy usually occurs in a young child with progressive primary TB; the presentation is that of reduced levels of consciousness with few focal signs and minimal meningism. Diffuse edema and white matter pallor with demyelination are found upon pathologic examination. The pathogenesis is uncertain but is presumed to be immune mediated. Diagnosis is important because anecdotal reports suggest a good response to corticosteroids.
• Tuberculomas are caseous foci with fibrous encapsulation in the brain parenchyma. They may coalesce together or grow in size, even during ongoing antitubercular therapy¹¹ and can involve the adjacent intracranial trunk artery, largely causing vasculitis¹² . Probable embolic spread of tuberculomas in the brain in multidrug resistant tubercular meningitis has been reported.¹³

Physical

Perform careful general, systemic, and neurologic examinations, looking especially for a BCG vaccination scar, lymphadenopathy, papilledema and tuberculomas during funduscopy, and meningismus.

• Visual findings
  • Apart from papilledema, fundus examination occasionally reveals a retinal tuberculoma or a small grayish-white choroidal nodule, highly suggestive of TB. These lesions are believed to be more common in miliary TB than in other forms of TB.
  • In children, fundus examination may reveal pallor of the disc.
  • Examination may elicit visual impairment.
• Neurologic findings
  • Cranial neuropathies, most often involving CN VI, may be noted. CNs III, IV, VII, and, less commonly, CNs II, VIII, X, XI, and XII, also may be affected.
  • Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and tetraparesis.
  • Tremor is the most common movement disorder seen in the course of TBM. In a smaller percentage of patients, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than adults. In addition, myoclonus and cerebellar dysfunction have been observed. Deep vascular lesions are more common among patients with movement disorders.

Causes

• Mycobacterium tuberculosis
  • The first description of TBM is credited to Robert Whytt, on the basis of his 1768 monograph, Observations of Dropsy in the Brain. TBM first was described as a distinct pathological entity in 1836, and Robert Koch demonstrated that TB was caused by M tuberculosis in 1882.
  • M tuberculosis is an aerobic gram-positive rod that stains poorly because of its thick cell wall that contains lipids, peptidoglycans, and arabinomannans.
    • Mycobacteria vary in appearance from spherical to short filaments, which may be branched. Although they appear as short to moderately long rods, they can be curved and frequently are seen in clumps. Individual bacilli generally are 0.5-1 µm in diameter and 1.5-10 µm long. They are nonmotile and do not form spores.
    • One of the distinct characteristics of mycobacteria is their ability to retain dyes within the bacilli that usually are removed from other microorganisms by alcohols and dilute solutions of strong mineral acids such as hydrochloric acid. This ability is attributed to a waxlike layer composed of long-chain fatty acids, the mycolic acids, in their cell wall. As a result, mycobacteria are termed acid-fast bacilli.
  • The mechanisms by which neurovirulence may occur are unknown.
• Risk factors
  • Human migration plays a large role in the epidemiology of TB. Massive human displacement during wars and famines has resulted in increased case rates of TB and an altered geographic distribution. With the advent of air travel, TB has a global presence. In the United States, the prevalence of TB, mostly in foreign-born persons, has steadily increased.
  • Once infected with M tuberculosis, HIV co-infection is the strongest risk factor for progression to active TB; the risk has been estimated to be as great as 10% per year, compared with 5-10% lifetime risk among persons with TB but not HIV infection.
    • Although patients who are HIV infected and also have TB are at increased risk for TBM, the clinical features and outcomes of TB do not seem to be altered by HIV.
    • Patients infected with HIV, especially those with AIDS, are at very high risk of developing active TB when exposed to a person with infectious drug-susceptible or drug-resistant TB. They have a higher incidence of drug-resistant TB, in part due to Mycobacterium avium-intracellulare, and have worse outcomes.
  • Predisposing factors for the development of active TB include malnutrition, alcoholism, substance abuse, diabetes mellitus, corticosteroid use, malignancy, head trauma, and HIV infection.
  • Homeless persons, people in correctional facilities, and residents of long-term care facilities also have a higher risk of developing active TB compared with the general population.

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